A total of 22 Lactobacillus strains, which were isolated from infant feces were evaluated for their probiotic potential along with resistance to low pH and bile salts. Eight isolates (L. reuteri 3M02 ...and 3M03, L. gasseri 4M13, 4R22, 5R01, 5R02, and 5R13, and L. rhamnosus 4B15) with high tolerance to acid and bile salts, and ability to adhere to the intestine were screened from 22 strains. Further, functional properties of 8 Lactobacillus strains, such as anti-oxidation, inhibition of α-glucosidase activity, cholesterol-lowering, and anti-inflammation were evaluated. The properties were strain-specific. Particularly, two strains of L. rhamnosus, 4B15 (4B15) and L. gasseri 4M13 (4M13) showed considerably higher anti-oxidation, inhibition of α-glucosidase activity, and cholesterol-lowering, and greater inhibition of nitric oxide production than other strains. Moreover, the two selected strains substantially inhibited the release of inflammatory mediators such as TNF-α, IL-6, IL-1β, and IL-10 stimulated the treatment of RAW 264.7 macrophages with LPS. In addition, whole genome sequencing and comparative genomic analysis of 4B15 and 4M13 indicated them as novel genomic strains. These results suggested that 4B15 and 4M13 showed the highest probiotic potential and have an impact on immune health by modulating pro-inflammatory cytokines.
Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous ...recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC).
TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years ≥20 years in Japan) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing.
Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9–30·2) for the talazoparib group and 24·6 months (14·4–30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months–not reached) for talazoparib plus enzalutamide and 21·9 months (16·6–25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51–0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3–4 event was anaemia (185 46% of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group.
Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations.
Pfizer.
PROpel met its primary endpoint showing statistically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in patients with ...first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status, with benefit observed in all prespecified subgroups. Here we report the final prespecified overall survival analysis.
This was a randomised, double-blind, phase 3 trial done at 126 centres in 17 countries worldwide. Patients with mCRPC aged at least 18 years, Eastern Cooperative Oncology Group performance status 0–1, a life expectancy of at least 6 months, with no previous systemic treatment for mCRPC and unselected by HRRm status were randomly assigned (1:1) centrally by means of an interactive voice response system–interactive web response system to abiraterone acetate (orally, 1000 mg once daily) plus prednisone or prednisolone with either olaparib (orally, 300 mg twice daily) or placebo. The patients, the investigator, and study centre staff were masked to drug allocation. Stratification factors were site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage. Radiographic progression-free survival was the primary endpoint and overall survival was a key secondary endpoint with alpha-control (alpha-threshold at prespecified final analysis: 0·0377 two-sided), evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03732820, and is completed and no longer recruiting.
Between Oct 31, 2018 and March 11, 2020, 1103 patients were screened, of whom 399 were randomly assigned to olaparib plus abiraterone and 397 to placebo plus abiraterone. Median follow-up for overall survival in patients with censored data was 36·6 months (IQR 34·1–40·3) for olaparib plus abiraterone and 36·5 months (33·8–40·3) for placebo plus abiraterone. Median overall survival was 42·1 months (95% CI 38·4–not reached) with olaparib plus abiraterone and 34·7 months (31·0–39·3) with placebo plus abiraterone (hazard ratio 0·81, 95% CI 0·67–1·00; p=0·054). The most common grade 3–4 adverse event was anaemia reported in 64 (16%) of 398 patients in the olaparib plus abiraterone and 13 (3%) of 396 patients in the placebo plus abiraterone group. Serious adverse events were reported in 161 (40%) in the olaparib plus abiraterone group and 126 (32%) in the placebo plus abiraterone group. One death in the placebo plus abiraterone group, from interstitial lung disease, was considered treatment related.
Overall survival was not significantly different between treatment groups at this final prespecified analysis.
Supported by AstraZeneca and Merck Sharp & Dohme.
In this study, a water-to-air type hollow-fiber membrane humidifier was built, and its humidification characteristics were experimentally investigated under various test conditions. A humidification ...module made of a porous hollow-fiber membrane in which hydrophilic and polymeric raw materials are mixed was used. Using the selected material, shell-and-tube structured hollow-fiber membrane module was fabricated and tested under various operating conditions. The experimental data showed that the proposed membrane modules exhibited 74.5%–91.7% humidification effectiveness and moisture transfer of 2.5–15.8 g/kg under various operating conditions; furthermore, the modules could provide humidifier performance with few temperature changes. The results of the parametric analysis indicated that the inlet water temperature was a critical factor affecting the humidification heating performance of the proposed system but did not show a clear effect of the water flow rate.
The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with ...apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg (n = 111) or placebo (n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio HR: 0.68; 95% confidence interval CI: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.
Androgen exerts its functions by binding with an androgen receptor (AR). It can activate many signaling pathways that are important to the progression of castration-resistant prostate cancer (CRPC). ...Here, we characterized the rapid proteomic changes seen at 5, 15, 30, and 60 min after the androgen treatment of VCaP cells via the tandem mass tag (TMT) labeling strategy. A total of 5529 proteins were successfully identified and quantified. Dynamic time profiling of protein expression patterns allowed us to identify five protein clusters involved in various stages of androgen-initiated signal transmission and processing. More details of protein functions and localization patterns, and our elucidation of an AR-interacting protein network, were obtained. Finally, we validated the expression level of AR-regulated proteins known to be significantly regulated in CRPC patients using the mouse xenograft model and patient samples. Our work offers a systematic analysis of the rapid proteomic changes induced by androgen and provides a global view of the molecular mechanisms underlying CRPC progression.
Androgen deprivation therapy (ADT) is used to block the release of androgen in prostate cancer to promote the regression of cancer cells, and hence, disease progression. Its indication has been ...widened from the metastatic setting to the localized setting in prostate cancer. Long-term ADT for suppressing androgen release leads to a rapid decrease in androgen, termed as andropause, resulting in several dose and duration dependent adverse effects, including cognitive dysfunction such as dementia. Many retrospective and prospective studies, as well as meta-analyses, have attempted to confirm the crucial relationship between ADT and cognitive dysfunction, but pro and contrary opinions regarding this issue are ongoing owing to the absence of randomized controlled trials. Additionally, several recent studies have suggested the negative effects of dose- and duration-dependent ADT on cognitive dysfunction, especially in 40–65-year-old patients with prostate cancer, who are currently active workers in the society. This review article discusses several studies examining the influence of ADT on mental health based on diverse significant perspectives, especially cognitive dysfunction.
We evaluated the impact of benign prostatic hyperplasia (BPH) and prostatitis on the risk of prostate cancer (PCa) in patients using nationally representative data of the Korean population from the ...National Health Insurance Service.
A total of 5,580,495 Korean men, aged >20 years, who had undergone health screening in 2009 were followed-up for 9 years until 2017. Multivariate adjusted Cox regression analysis was conducted to determine the hazard ratio (HR) and 95% confidence interval (CI) for the association between BPH and/or prostatitis and PCa. The HR for PCa according to the presence of BPH and/or prostatitis was stratified by a combination of BPH and prostatitis in multivariable-adjusted models.
The HR for PCa significantly increased in patients with BPH and prostatitis than in patients without BPH and prostatitis (adjusted HR, 1.626; 95% CI, 1.567-1.688 and adjusted HR, 1.557; 95% CI, 1.500-1.618, respectively). In particular, for the combination of BPH and prostatitis, the adjusted HR was 1.856 (95% CI, 1.743-1.976), which was the highest when a diagnosis of both BPH and prostatitis was made.
BPH and/or prostatitis are associated with an increased incidence for PCa in Korean patients, which is likely associated with similar effects to prostate-specific antigen (PSA) screening, so care must be taken in the interpretation. However, if follow-up survival studies demonstrate differences between the two groups (BPH and prostatitis vs. general), it could be one of the evidence for the introduction of PSA screening in Korea.
This study aimed to identify metabolic genes associated with non-metastatic prostate cancer progression using The Cancer Genome Atlas (TCGA) datasets and validate their prognostic role by assessing ...patients' immunohistochemical prostatectomy specimens.
Several metabolic candidate genes analyzed were highly correlated with cancer progression to biochemical recurrence (BCR) and deaths in 335 patients' genetic information from TCGA datasets. Those candidate genes and their expressions in tissue specimens were validated retrospectively by immunohistochemical analysis of radical prostatectomy specimens collected from 514 consecutive patients with non-metastatic prostate cancer between 2000 and 2015. The Cox proportional-hazards model was used to predict the prognostic role of each candidate gene expression in BCR and survival prognoses with a statistical significance of p-value <0.05. Twenty metabolic genes were identified by own developed software (Targa; https://github.com/cgab-ncc/TarGA), whose median expression levels consistently increased with cancer progression to the BCR and deaths.
Five metabolic genes (
,
,
,
, and
) were found to be significantly involved in the overall survival in the TCGA dataset. The immunohistochemical validation and clinicopathological data showed that
(hazard ratio HR, 1.002; 95% confidence interval CI, 1.001-1.003) and
(HR, 1.010; 95% CI, 1.003-1.017) remained significant factors for BCR and cancer-specific survival, respectively, in the multivariate analysis even after adjusting for confounding clinicopathological parameters (p<0.05).
and
showed significant prognostic factors of disease progression, even after adjustment for confounding clinicopathological parameters in non-metastatic prostate cancer.
PDF
